Immune response to certain antigens that are otherwise weakly immunogenic can be enhanced through the use of vaccine adjuvants. Such adjuvants potentiate the immune response to specific antigens and are therefore the subject of considerable interest and study within the medical community.
Research has permitted development of vaccines possessing antigenic epitopes that were previously impossible to produce. For example, currently available vaccine candidates include synthetic peptides mimicking streptococcal, gonococcal, and malarial antigens. These purified antigens are generally weak immunogens, however, that require adjuvants in order to evoke protective immunity. However, conventional vaccine adjuvants possess a number of drawbacks that limit their overall use and effectiveness.
Substances that stimulate immune cells in vitro exhibit similar immunostimulatory effects in vivo. These compounds, such as recombinant cytokines, pathogen products (e.g. toxins, lipids, proteins/peptides, carbohydrates and nucleic acids) and other mammalian-derived immunostimulatory molecules (e.g. heat shock proteins, complement, immune complexes and proteoglycans) all induce a measurable pro-inflammatory response both in vitro and in vivo.
Historically, the classic adjuvants have been Freund's complete or incomplete (i.e., without mycobacteria) adjuvants. Edmund Coley described the potential of Coley's toxin for cancer immunotherapy. Other materials, such as mineral oil and aluminum hydroxide, have also been used as adjuvants, but they invariably suffer from disadvantages. For example, mineral oil is known to produce tissue irritation and to be potentially oncogenic. Alum, the only approved adjuvant in the United States, also induces granulomas at the inoculation site and furthermore it does not effectively induce cell-mediated immunity. Moreover, many of the adjuvants currently available have limited utility because they contain components, that are not metabolizable in humans. Additionally, most adjuvants are difficult to prepare in that they may require time consuming procedures and the use, in some cases, of elaborate and expensive equipment to formulate a vaccine and adjuvant system.
Immunological adjuvants are described in “Current Status of Immunological Adjuvants”, Ann. Rev. Immunol., 1986, 4, pp. 369-388, and “Recent Advances in Vaccine Adjuvants and Delivery Systems” by Derek T O'Hagan and Nicholas M. Valiente. See also U.S. Pat. Nos. 4,806,352; 5,026,543; and 5,026,546 for disclosures of various vaccine adjuvants appearing in the patent literature.
Immunostimulatory oligonucleotides and polynucleotides are described in PCT WO 98/55495 and PCT WO 98/16247. U.S. Patent Application No. 2002/0164341 describes adjuvants including an unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant. U.S. Patent Application No. 2002/0197269 describes compositions comprising an antigen, an immunogenic CpG-ODN and a polycationic polymer.
Tryptanthrin (indolo-[2,1-b]quinazolin-6,12-dione) is a material that is produced naturally in some plant species, and has been produced synthetically by a base catalyzed condensation of isatin and isatoic anhydride. Tryptanthrin and some of its analogs have been shown to exhibit some antimicrobial activity against various bacterial and yeast species. Mitscher et al., “Antimicrobial Agents From Higher Plants. New Synthesis and Bioactivity of Tryptanthrin (Indolo-[2,1-b]-quinazolin-6,12-dione) and its Analogs,” Heterocycles 15(2):1017-1021 (1981)).
The synthesis of indolo[2,1-b]quinazoline-6,12-dione derivatives and their use in the treatment of pathogenic mycobacterial infections are described in U.S. Pat. No. 5,441,955. U.S. Pat. No. 6,284,772 discloses the use of indolo[2,1-b]quinazoline-6,12-dione derivatives and prodrugs for treatment of malaria.
There has been an effort to find new adjuvants for vaccines that would overcome the drawbacks and deficiencies of conventional adjuvants. In particular, an adjuvant formulation that elicits potent cell-mediated and humoral immune responses to a wide range of antigens in humans and domestic animals, but lacking the side effects of conventional adjuvants, such as Freund's complete adjuvant, would be highly desirable. There also is a need for new small molecule immune potentiators.